Identification of any publication in this section or any section of this application is not an admission that such publication is prior art to the present invention.
A process for making the compound of Formula I, (1R,2S,5S)—N-[(1S)-3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3-[(2S)-2-[[[(1,1-dimethylethyl)amino]carbonyl]-amino]-3,3-dimethyl-1-oxobutyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxamide is described in U.S. Pat. No. 7,012,066 (the '066 patent), Example XXIV, beginning at Column 448 therein. Additional processes for the preparation of the compounds of Formula I are described in published U.S. patent application nos. 2005/0249702, published Nov. 10, 2005, and 2005/0059800, published Mar. 17, 2005.
In general, the process for the preparation of compounds of Formula I is illustrated in Scheme I:

In accordance with Scheme I, compounds of formula I have been prepared by coupling the compound of Formula Ia with the compound of Formula Ib, preferably, as illustrated in published U.S. application no. 2005/0059800, by treating an acetonitrile solution of 2,6 lutidine and the compound of Formula Ia with an acetonitrile solution containing the compound of Formula Ib, ethyl[(3-dimethylamino)propyl]carbodiimide hydrochloride salt (EDCI-HCl), and 1-hydroxybenzotriazole hydrate (HOBt). After the coupling reaction is complete the reaction mixture provided by Step 1 is worked up by adding methyl-tertiarybutyl ether (MTBE), adjusting the pH with HCl, extracting with sodium bicarbonate and concentrating the organic solution. The concentrate is then diluted with acetonitrile and reconcentrated, then treated with aqueous lithium hydroxide followed by an HCl/isopropyl acetate solution to liberate the free acid, and finally treated with L-α-methylbenzylamine to precipitate the 1c salt form of the coupled product, wherein “salt” is the counter ion of Formula 1f (L-α-methylbenzylamine).

As illustrated in Scheme I, the compound of Formula I is provided from the compound of Formula Ic using one of two processes. In one process, shown in Steps 2′a and 2′ b, a three step procedure, the free acid is generated from the compound of Formula Ic (by treatment with acid, subsequently removing the L-α-methylbenxylamine counterion). The free acid form of Ic is coupled with amine Id′ followed by oxidation of the coupled product.
In an alternative process, shown in Scheme I as Step 2, the free acid form of compound Ic is coupled with the amine Id to provide the compound of Formula I directly. Accordingly, with reference to the '066 patent, the coupling process of Step 2 can carried out by treating a DMF/CH2Cl2 solution of the free acid form of compound Ic with amine Id′ in the presence of EDCI, HOBt, and N-methylmorpholine to provide the coupled product. After the coupling reaction is complete, the reaction mixture is concentrated, treated with aqueous HCl and the aqueous layer is extracted with dichloromethane. The dichloromethane extract is washed in turn with aqueous NaHCO3, aqueous HCl, and brine, dried with MgSO4, and dried to a solid under vacuum. The alcohol functional group of the coupled product is then oxidized to provide the compound of Formula I. Oxidation can be carried out by treatment with EDCI in mixed toluene/DMSO in the presence of dichloroacetic acid.
In accordance with the foregoing, the previous processes for the preparation of the compound of Formula I using Scheme I requires the use of 1-hydroxy benzotriazole in the first amidation reaction coupling the compounds of formula Ia and Ib to form the intermediate compound of formula Ic. Since HOBt is classified as a reactive solid, and therefor storage and transport of the material is regulated, its use in commercial scale manufacture entails difficulties in handling and storage, and therefore it is desirable to minimize the number of steps in which it is employed. Moreover, when generating the free acid form of the compound of Formula Ic, a solvent distillation step and/or a solvent swap step is needed to improve reaction efficiency, either of which increases free acid degradation. Additionally, the process of Scheme I utilizes the formation of α-methylbenzylamine salts to provide the intermediate Ic in sufficiently pure form that it can be used in the subsequent process step, however, the L-α-methylbenzylamine counterion has been found to react with the isolation solvent, for example, isopropylacetate, to form an N-acetyl-α-methylbenzylamine impurity. Furthermore, the L-α-methylbenzylamine counterion has been found to compete with the amines of Formulae Id and Id′ in the subsequent coupling reaction, and to form undesirable byproducts under the reaction conditions of interest. Thus, when the salt intermediate is converted to the free acid, the amine must be separated from the free acid prior to carrying out the second coupling reaction when such processing schemes are employed.
What is needed is a process for providing the compound of Formula I which minimizes the use of HOBT and which obviates the need to regenerate the free acid form of intermediate compound Ic to carry out the second coupling step (Step 2) illustrated in Scheme I.